Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 22
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mater Sci Eng C Mater Biol Appl ; 119: 111501, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33321601

RESUMO

Current outbreaks associated with drug-resistant clinical strains are demanding for the development of broad-spectrum antibacterial agents. The bactericidal materials should be eco-friendly, economical and effective to suppress bacterial growth. Thus, in this work, diameter controlled spherical Cucore-Agshell nanoparticles (Ag@CuNPs) with diameter ranging from 70 to 100 nm by one-step co-reduction approach were designed and synthesized. The Ag@CuNPs were homogenous, stable, and positively charged. The 70 nm Ag@CuNPs showed a consistent and regular Ag shielding. We observed the 100 nm Ag@CuNPs achieved symmetrical doped Ag clusters on the Cu core surface. We used Gram-positive and Gram-negative models strains to test the wide-spectrum antibacterial activity. The Ag@CuNPs showed detrimental microbial viability in a dose-dependent manner; however, 70 nm Ag@CuNPs were superior to those of 100 nm Ag@CuNPs. Initially, Ag@CuNPs attached and translocated the membrane surface resulting in bacterial eradication. Our analyses exhibited that antibacterial mechanism was not governed by the bacterial genre, nonetheless, by cell type, morphology, growing ability and the NPs uptake capability. The Ag@CuNPs were highly tolerated by human fibroblasts, mainly by the use of starch as glucosidic capper and stabilizer, suggesting optimal biocompatibility and activity. The Ag@CuNPs open up a novel platform to study the potential action of bimetallic nanoparticles and their molecular role for biomedical, clinical, hospital and industrial-chemical applications.

2.
mSystems ; 5(6)2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33172970

RESUMO

Marine microbes are known to degrade hydrocarbons; however, microbes inhabiting deep-sea sediments remain largely unexplored. Previous studies into the classical pathways of marine microbial metabolism reveal diverse chemistries; however, metabolic profiling of marine microbes cultured with hydrocarbons is limited. In this study, taxonomic (amplicon sequencing) profiles of two environmental deep-sea sediments (>1,200 m deep) were obtained, along with taxonomic and metabolomic (mass spectrometry-based metabolomics) profiles of microbes harbored in deep-sea sediments cultured with hydrocarbons as the sole energy source. Samples were collected from the Gulf of México (GM) and cultured for 28 days using simple (toluene, benzene, hexadecane, and naphthalene) and complex (petroleum API 40) hydrocarbon mixtures as the sole energy sources. The sediment samples harbored diverse microbial communities predominantly classified into Woeseiaceae and Kiloniellaceae families, whereas Pseudomonadaceae and Enterobacteriaceae families prevailed after sediments were cultured with hydrocarbons. Chemical profiling of microbial metabolomes revealed diverse chemical groups belonging primarily to the lipids and lipid-like molecules superclass, as well as the organoheterocyclic compound superclass (ClassyFire annotation). Metabolomic data and prediction of functional profiles indicated an increase in aromatic and alkane degradation in samples cultured with hydrocarbons. Previously unreported metabolites, identified as intermediates in the degradation of hydrocarbons, were annotated as hydroxylated polyunsaturated fatty acids and carboxylated benzene derivatives. In summary, this study used mass spectrometry-based metabolomics coupled to chemoinformatics to demonstrate how microbes from deep-sea sediments could be cultured in the presence of hydrocarbons. This study also highlights how this experimental approach can be used to increase the understanding of hydrocarbon degradation by deep-sea sediment microbes.IMPORTANCE High-throughput technologies and emerging informatics tools have significantly advanced knowledge of hydrocarbon metabolism by marine microbes. However, research into microbes inhabiting deep-sea sediments (>1,000 m) is limited compared to those found in shallow waters. In this study, a nontargeted and nonclassical approach was used to examine the diversity of bacterial taxa and the metabolic profiles of hydrocarbon-degrading deep-sea microbes. In conclusion, this study used metabolomics and chemoinformatics to demonstrate that microbes from deep-sea sediment origin thrive in the presence of toxic and difficult-to-metabolize hydrocarbons. Notably, this study provides evidence of previously unreported metabolites and the global chemical repertoire associated with the metabolism of hydrocarbons by deep-sea microbes.

3.
Sci Rep ; 10(1): 14526, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32884027

RESUMO

Gulf War illness (GWI) afflicts military personnel who served during the Persian Gulf War and is notable for cognitive deficits, depression, muscle pain, weakness, intolerance to exercise, and fatigue. Suspect causal agents include the chemicals pyridostigmine (PB), permetrim (PM) and N,N-diethyl-m-toluamide (DEET) used as protectants against insects and nerve gases. No pre-clinical studies have explored the effects on skeletal muscle (SkM). Young male rats were provided PB, PM and DEET at equivalent human doses and physical restraint (to induce stress) for 3 weeks followed a 3-week recovery. GWI gastrocnemius weight was ~ 35% lower versus controls, which correlated with decreases in myofiber area, limb strength, and treadmill time/distance. In GWI rats, SkM fiber type relative abundance changed towards slow type I. Muscle wasting pathway proteins were upregulated while those that promote growth decreased as did mitochondrial endpoints and muscle ATP levels. Proteomic analysis of SkM also documented unique alterations in mitochondrial and metabolic pathways. Thus, exposure to GWI chemicals/stress adversely impacts key metabolic pathways leading to muscle atrophy and loss of function. These changes may account for GWI Veterans symptoms.

5.
Pharmacol Res ; 151: 104540, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31722227

RESUMO

Currently, there is great interest in identifying endogenous (i.e. physiological) stimulators of mitochondrial biogenesis (MB), in particular, those that may mediate the effects of exercise. The molecular size of the cacao flavanols (epicatechin and catechin) highly resembles that of sterols and epicatechin has been reported to activate cells surface receptors leading to the stimulation of MB in endothelial and skeletal muscle cells translating into enhanced exercise capacity. We therefore hypothesize, that epicatechin may be acting as a structural mimic of an as yet unknown sterol capable of stimulating MB. We developed a new synthetic process for obtaining enantiomerically pure preparations of (-)-epicatechin and (+)-epicatechin. Applying spatial analytics and molecular modeling, we found that the two isoforms of epicatechin, (-) and (+), have a structural resemblance to 11-ß-hydroxypregnenolone, a sterol with no previously described biological activity. As reported in this proof-of-concept study performed in primary cultures of endothelial and muscle cells, 11-ß-hydroxypregnenolone is one of the most potent inducers of MB as significant activity can be detected at femtomolar levels. The relative potency of (-)/(+)-epicatechin isoforms and on inducing MB correlates with their degree of spatial homology towards the 11-ß-hydroxypregnenolone. On the basis of these results, the detailed in vivo characterization of the potential for these sterols to act as endogenous modulators of MB is warranted.

6.
Carbohydr Polym ; 206: 455-467, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30553345

RESUMO

This study sought to improve the handling, stability to aqueous medium and healing properties of alginate-based three-dimensional structures to be applied as wound scaffolds. Thus, Ca-alginate was plasticized with PEG-methyl ether methacrylate (PEGMA) and blended with the freeze-dried gel of A. vera and aqueous leaves extracts of M. oleifera. Ca-alginate-PEGMA scaffolds remained structurally stable almost four times longer than pure alginate materials, while a high porous architecture required for tissue scaffolding applications was maintained after alginate plasticization with PEGMA. A. vera increased the water uptake capability of the scaffolds and M. oleifera provided antioxidant capacity, anti-inflammatory properties and antimicrobial activity against S. aureus. Blending 1% (w/v) A. vera and 1% (w/v) M. oleifera with Ca-alginate-PEGMA, significantly increased the scaffolds cell proliferation (after 10 days of evaluation), compared with scaffolds without plant extracts. The experimental results showed that Ca-alginate-PEGMA/A. vera/M. oleifera biocomposites have great potential for wound healing applications.


Assuntos
Alginatos/farmacologia , Aloe/química , Metacrilatos/farmacologia , Moringa oleifera/química , Extratos Vegetais/farmacologia , Polietilenoglicóis/farmacologia , Cicatrização/efeitos dos fármacos , Alginatos/química , Antibacterianos/química , Antibacterianos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Humanos , Metacrilatos/química , Extratos Vegetais/química , Folhas de Planta/química , Preparações de Plantas/química , Preparações de Plantas/farmacologia , Polietilenoglicóis/química , Porosidade , Staphylococcus aureus/efeitos dos fármacos
7.
Diabetes Res Clin Pract ; 143: 79-87, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29936251

RESUMO

OBJECTIVES: To determine and compare the prevalence and risk factors of metabolic syndrome (MS) among Tarahumara Indians living in rural and urban communities. METHODS: Conducted in 2010, this cross-sectional study included 204 Tarahumara (100 urban and 104 rural individuals 18-75 years old [yo]). Data obtained includes: Anthropometric, lifestyle, blood pressure (BP) and fasting blood tests. Analyses were stratified by gender and age. RESULTS: The total prevalence of MS in rural and urban Tarahumara were 41% and 28% (p = 0.04), respectively. In urban cohorts, the prevalence of MS increased linearly with age. Women presented with a higher MS prevalence than men in urban (44.6% vs. 34.3%, p = 0.4) and rural (50% vs. 12.5%, p = 0.0001) cohorts. In men, urban residents presented with a higher MS prevalence vs. rural subjects; The same was not true for women. Age-related increment in waist circumference was linear and significantly higher in urban men compared to their rural counterpart (urban 6.5 [95% CI 4.24-8.79] vs. rural 2.7 [95% CI 1.19-4.24] centimeters/decade, p < 0.05). Multivariate analysis showed a significant relationship between urban residency and MS in men, but not in women. CONCLUSION: The overall prevalence of MS is higher in women than men, but the latter are more susceptible to the urbanization-associated worsening of cardiometabolic health.


Assuntos
Síndrome Metabólica/etiologia , Adolescente , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Síndrome Metabólica/epidemiologia , México , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , População Rural , População Urbana , Adulto Jovem
8.
Bioorg Med Chem Lett ; 28(4): 658-663, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29395974

RESUMO

To potentially identify proteins that interact (i.e. bind) and may contribute to mediate (-)-epicatechin (Epi) responses in endothelial cells we implemented the following strategy: 1) synthesis of novel Epi derivatives amenable to affinity column use, 2) in silico molecular docking studies of the novel derivatives on G protein-coupled estrogen receptor (GPER), 3) biological assessment of the derivatives on NO production, 4) implementation of an immobilized Epi derivative affinity column and, 5) affinity column based isolation of Epi interacting proteins from endothelial cell protein extracts. For these purposes, the Epi phenol and C3 hydroxyl groups were chemically modified with propargyl or mesyl groups. Docking studies of the novel Epi derivatives on GPER conformers at 14 ns and 70 ns demostrated favorable thermodynamic interactions reaching the binding site. Cultures of bovine coronary artery endothelial cells (BCAEC) treated with Epi derivatives stimulated NO production via Ser1179 phosphorylation of eNOS, effects that were attenuated by the use of the GPER blocker, G15. Epi derivative affinity columns yielded multiple proteins from BCAEC. Proteins were electrophoretically separated and inmmunoblotting analysis revealed GPER as an Epi derivative binding protein. Altogether, these results validate the proposed strategy to potentially isolate and identify novel Epi receptors that may account for its biological activity.


Assuntos
Catequina/análogos & derivados , Catequina/farmacologia , Estrogênios/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Sítios de Ligação , Catequina/síntese química , Catequina/química , Bovinos , Cromatografia de Afinidade , Vasos Coronários/metabolismo , Células Endoteliais/metabolismo , Estrogênios/síntese química , Estrogênios/química , Simulação de Acoplamento Molecular , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Receptores Estrogênicos/química , Receptores Acoplados a Proteínas-G/química , Estereoisomerismo , Relação Estrutura-Atividade
9.
Eur J Pharmacol ; 822: 95-107, 2018 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-29355558

RESUMO

We have reported on the capacity of (-)-epicatechin ((-)-EPI) to stimulate mitochondrial biogenesis (MiB) in mouse skeletal muscle (SkM). However, the mechanisms mediating the effects of (-)-EPI are not fully understood. We previously identified a role of the G-protein coupled estrogen receptor (GPER) in modulating the vascular effects of (-)-EPI. We therefore tested the hypothesis that GPER mediates (at least in part) the stimulatory effects of (-)-EPI on MiB in SkM cells. As an in vitro model, we employed mouse SkM-derived C2C12 myoblasts differentiated into myotubes. Using confocal microscopy, we detected GPER at the cell surface and cytoplasm in C2C12 myotubes. Treatment with (-)-EPI (3 and 10µM) resulted in the stimulation of MiB as per increases in mitochondrial inner (MitoTracker Red FM fluorescence staining) and outer membrane (porin protein levels) markers, transcription factors involved in MiB stimulation (i.e., nuclear respiratory factor-2 [NRF-2] and mitochondrial transcription factor A [TFAM] protein levels) and citrate synthase (CS) activity levels. (-)-EPI-treated myotubes were longer and wider compared to vehicle-treated myotubes. The effects of (-)-EPI on myotube mitochondria and cell size were larger in magnitude to those observed with the GPER agonist G-1. The chemical blockade and down-regulation (siRNA) of GPER evidenced a partial and complete blockade of measured endpoints following (-)-EPI- or G-1-treatment, respectively. Altogether, results indicate that GPER is expressed in muscle cells and appears to mediate to a significant extent, the stimulatory effects of (-)-EPI on MiB. Thus, GPER activation may account for the stimulatory effects of (-)-EPI on SkM structure/function.


Assuntos
Catequina/farmacologia , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Biogênese de Organelas , Receptores Estrogênicos/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ligantes , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Mioblastos/citologia , Mioblastos/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos
10.
Eur J Pharmacol ; 818: 335-342, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29126791

RESUMO

The production of nitric oxide (NO) by nitric oxide synthases (NOS) depends on the bioavailability of L-arginine as NOS competes with arginase for this common substrate. As arginase activity increases, less NO is produced and adverse cardiovascular consequences can emerge. (-)-Epicatechin (EPI), the most abundant flavonoid in cacao, has been reported to stimulate endothelial and neuronal NOS expression and function leading to enhanced vascular function and cardioprotective effects. However, little is known about the effects of EPI on myocardial arginase activity. The aim of the present study was to determine if EPI is able to interact and modulate myocardial arginase and NOS expression and activity. For this purpose, in silico modeling, in vitro activity assays and a rat model of ischemia/reperfusion injury were used. In silico and in vitro results demonstrate that EPI can interact with arginase and significantly decrease its activity. In vivo, 10 days of EPI pretreatment reduces ischemic myocardium arginase expression while increasing NOS expression and phosphorylation levels. Altogether, these results may partially account for the cardioprotective effects of EPI.


Assuntos
Arginase/antagonistas & inibidores , Cardiotônicos/farmacologia , Catequina/farmacologia , Inibidores Enzimáticos/farmacologia , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Arginase/química , Arginase/metabolismo , Catequina/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/metabolismo , Simulação de Acoplamento Molecular , Miocárdio/enzimologia , Óxido Nítrico Sintase/metabolismo , Conformação Proteica
11.
Food Funct ; 9(1): 307-319, 2018 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-29171848

RESUMO

We reported that (-)-epicatechin can stimulate mitochondria biogenesis and improve metabolism. However, preliminary studies indicate that the (+) stereoisomer form may be more potent. We evaluated in a preliminary manner, the pharmacokinetics (PK) and initial safety analysis of (+)-epicatechin ((+)-Epi) in healthy and pre-diabetic subjects. Using a mouse model of diet-induced obesity and insulin resistance, we also evaluated the metabolic effects of (+)-Epi vs. (+)-catechin (Cat) to determine class effects. In the Phase I PK study, subjects were provided a single incremental oral dose of (+)-Epi (10, 30 or 100 mg). For the PD study, subjects were provided a single 30 mg dose per day for 7 days. Blood samples were collected and safety measures were performed. Incremental doses of (+)-Epi increase the half-life of blood metabolites from 1.2-4.9 h. The compound was well tolerated and no adverse effects were reported. Seven day dosing of pre-diabetic subjects led to tendencies for reductions in circulating levels of tumor necrosis factor-α and monocyte chemoattractant protein-1, which returned to baseline by 7 days after treatment. In animals, 2 weeks of oral dosing (0.003, 0.01, 0.03, 0.1 and 0.3 mg kg-1 day-1) dose dependently improved metabolism-related endpoints (weight gain, glucose, cholesterol, triglyceride, with thresholds as low as 0.01 mg kg-1 day-1). Cat yielded no effects at 0.1 mg kg-1 day-1. Results indicate that (+)-Epi evidences a favorable PK and safety profile. Using a pre-clinical model, the compound positively modulates metabolism, which may link to mitochondrial effects. Effects are not due to general antioxidant actions, as Cat yielded no effects.


Assuntos
Catequina/farmacocinética , Estado Pré-Diabético/tratamento farmacológico , Adulto , Idoso , Animais , Glicemia , Catequina/administração & dosagem , Catequina/sangue , Colesterol , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Projetos Piloto , Estado Pré-Diabético/sangue , Estado Pré-Diabético/metabolismo , Triglicerídeos , Adulto Jovem
12.
J Nanobiotechnology ; 15(1): 10, 2017 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-28143540

RESUMO

BACKGROUND: Neovascularization over dental implants is an imperative requisite to achieve successful osseointegration onto implanted materials. The aim of this study was to investigate the effects on in vitro angiogenesis of anodized 70 nm diameter TiO2 nanotubes (NTs) on Ti6Al4V alloy synthesized and disinfected by means of a novel, facile, antibacterial and cost-effective method using super oxidized water (SOW). We also evaluated the role of the surface roughness and chemical composition of materials of materials on angiogenesis. METHODS: The Ti6Al4V alloy and a commercially pure Ti were anodized using a solution constituted by SOW and fluoride as electrolyte. An acid-etched Ti6Al4V was evaluated to compare the effect of micro-surface roughness. Mirror-polished materials were used as control. Morphology, roughness, chemistry and wettability were assessed by field emission scanning electron microscopy (FE-SEM), transmission electron microscopy, atomic force microscopy, energy dispersive X-ray spectroscopy (EDX) and using a professional digital camera. Bovine coronary artery endothelial cells (BCAECs) were seeded over the experimental surfaces for several incubation times. Cellular adhesion, proliferation and monolayer formation were evaluated by means of SEM. BCAEC viability, actin stress fibers and vinculin cellular organization, as well as the angiogenic receptors vascular endothelial growth factor 2 (VEGFR2) and endothelial nitric oxide synthase (eNOS) were measured using fluorescence microscopy. RESULTS: The anodization process significantly increased the roughness, wettability and thickness of the oxidized coating. EDX analysis demonstrated an increased oxygen (O) and decreased carbon (C) content on the NTs of both materials. Endothelial behavior was solidly supported and improved by the NTs (without significant differences between Ti and alloy), showing that endothelial viability, adhesion, proliferation, actin arrangement with vinculin expression and monolayer development were evidently stimulated on the nanostructured surface, also leading to increased activation of VEGFR2 and eNOS on Ti6Al4V-NTs compared to the control Ti6Al4V alloy. Although the rougher alloy promoted BCAECs viability and proliferation, filopodia formation was poor. CONCLUSION: The in vitro results suggest that 70 nm diameter NTs manufactured by anodization and cleaned using SOW promotes in vitro endothelial activity, which may improve in vivo angiogenesis supporting a faster clinical osseointegration process.


Assuntos
Indutores da Angiogênese/farmacologia , Nanotubos/química , Neovascularização Fisiológica/efeitos dos fármacos , Titânio/química , Animais , Bovinos , Adesão Celular , Proliferação de Células , Células Cultivadas , Vasos Coronários/citologia , Implantes Dentários , Células Endoteliais/efeitos dos fármacos , Microscopia de Força Atômica , Microscopia Eletrônica de Varredura , Óxido Nítrico Sintase Tipo III/metabolismo , Tamanho da Partícula , Espectrometria por Raios X , Propriedades de Superfície , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Molhabilidade
13.
Food Funct ; 7(9): 3686-93, 2016 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-27491778

RESUMO

In heart failure patients the consumption of (-)-epicatechin ((-)-Epi)-rich cocoa can restore skeletal muscle (SkM) mitochondrial structure and decrease biomarkers of oxidative stress. However, nothing is known about its effects on exercise capacity and underlying mechanisms in normal, sedentary subjects. Twenty normal, sedentary subjects (∼50 years old) were randomized to placebo or dark chocolate (DC) groups and consumed 20 g of the products for 3 months. Subjects underwent before and after treatment, bicycle ergometry to assess VO2 max and work, SkM biopsy to assess changes in mitochondrial density, function and oxidative stress and blood sampling to assess metabolic endpoints. Seventeen subjects completed the trial. In the DC group (n = 9), VO2 max increased (17% increase, p = 0.056) as well as maximum work (watts) achieved (p = 0.026) with no changes with placebo (n = 8). The DC group evidenced increases in HDL levels (p = 0.005) and decreased triglycerides (p = 0.07). With DC, SkM evidenced significant increases in protein levels for LKB1, AMPK and PGC1α and in their active forms (phosphorylated AMPK and LKB1) as well as in citrate synthase activity while no changes were observed in mitochondrial density. With DC, significant increases in SkM reduced glutathione levels and decreases in protein carbonylation were observed. Improvements in maximum work achieved and VO2 max may be due to DC activation of upstream control systems and enhancement of SkM mitochondria efficiency. Larger clinical studies are warranted to confirm these observations.


Assuntos
Cacau/metabolismo , Chocolate/análise , Exercício Físico , Músculo Esquelético/metabolismo , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Comportamento Sedentário , Triglicerídeos/metabolismo
14.
Med Hypotheses ; 91: 86-89, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27142152

RESUMO

Diabetes has become a worldwide epidemic, and is growing at a rapid rate with drastic projections for developing countries. Mexico occupies the ninth place worldwide for type 2 diabetes prevalence, and in the foreseeable future, it is expected rise to the seventh place. Myocardial infarction is the most common cause of death in these patients. Although several drugs are approved for the treatment of type 2 diabetes that reduce factors associated with myocardial infarction, an excess risk of death is still present. In this regard, the American Diabetes Association recommends metformin (oral glucose lowering drug) as the first-line therapy in type 2 diabetic subjects, based on its amply confirmed positive metabolic effects; however, its capacity to reduce cardiovascular mortality in type 2 diabetic subjects is inconclusive. Thus, mortality reduction in these patients has been an elusive goal, and is therefore, imperative to evaluate new pharmacological interventions that may favorably impact mortality in these individuals. On the other hand, epidemiological studies have suggested that moderate consumption of cacao-derived products (i.e., chocolate and cocoa) may reduce the risk of diabetes, myocardial infarction, and cardiovascular disease-associated mortality. Moreover, interventional studies have also suggested that dark chocolate and cocoa consumption is vasculoprotective in normal and type 2 diabetic individuals. (-)-Epicatechin ((-)-EPI) is the main flavanol present in cacao, and suggested to be responsible for the beneficial effects observed after dark chocolate/cocoa consumption. Interestingly, in vivo studies have evidenced the capacity of (-)-EPI to reduce infarct size, and preserve cardiac mechanics in rodent models of ischaemia-reperfusion injury. Nonetheless, long-term studies using (-)-EPI and evaluating its effects on mortality are lacking. Thus, based on their particular properties, it is valid to speculate that (-)-EPI and metformin in conjunction may favorably impact mortality in type 2 diabetic individuals. Here, we provide the evidence that allow us to propose our hypothesis, and further suggest a reasonable way to perform the study needed for such investigation.


Assuntos
Catequina/uso terapêutico , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/terapia , Metformina/uso terapêutico , Animais , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/prevenção & controle , Chocolate , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/prevenção & controle , Humanos , Infarto do Miocárdio/metabolismo , Ratos , Traumatismo por Reperfusão/patologia
15.
Diab Vasc Dis Res ; 13(3): 201-10, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26993496

RESUMO

(-)-Epicatechin increases indicators associated with mitochondrial biogenesis in endothelial cells and myocardium. We investigated endothelial nitric oxide synthase involvement on (-)-epicatechin-induced increases in indicators associated with mitochondrial biogenesis in human coronary artery endothelial cells cultured in normal-glucose and high-glucose media, as well as to restore indicators of cardiac mitochondria from the effects of simulated diabetes. Here, we demonstrate the role of endothelial nitric oxide synthase on (-)-epicatechin-induced increases in mitochondrial proteins, transcription factors and sirtuin 1 under normal-glucose conditions. In simulated diabetes endothelial nitric oxide synthase function, mitochondrial function-associated and biogenesis-associated indicators were adversely impacted by high glucose, effects that were reverted by (-)-epicatechin. As an animal model of type 2 diabetes, 2-month old C57BL/6 mice were fed a high-fat diet for 16 weeks. Fasting and fed blood glucose levels were increased and NO plasma levels decreased. High-fat-diet-fed mice myocardium revealed endothelial nitric oxide synthase dysfunction, reduced mitochondrial activity and markers of mitochondrial biogenesis. The administration of 1 mg/kg (-)-epicatechin for 15 days by oral gavage shifted these endpoints towards control mice values. Results suggest that endothelial nitric oxide synthase mediates (-)-epicatechin-induced increases of indicators associated with mitochondrial biogenesis in endothelial cells. (-)-Epicatechin also counteracts the negative effects that high glucose or simulated type 2 diabetes has on endothelial nitric oxide synthase function.


Assuntos
Catequina/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Células Endoteliais/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Miocárdio/enzimologia , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Células Endoteliais/enzimologia , Células Endoteliais/patologia , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/enzimologia , Mitocôndrias Cardíacas/patologia , Miocárdio/patologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/genética , Biogênese de Organelas , Fosforilação , Interferência de RNA , Transdução de Sinais/efeitos dos fármacos , Transfecção
16.
Oxid Med Cell Longev ; 2015: 756294, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26290682

RESUMO

OBJECTIVE: To evaluate the effects of ezetimibe/simvastatin (EZE/SIMV) and rosuvastatin (ROSUV) on oxidative stress (OS) markers in patients with diabetic polyneuropathy (DPN). METHODS: We performed a randomized, double-blind, placebo-controlled phase III clinical trial in adult patients with Type 2 Diabetes Mellitus (T2DM) and DPN, as evaluated by composite scores and nerve conduction studies (NCS). Seventy-four subjects with T2DM were allocated 1 : 1 : 1 to placebo, EZE/SIMV 10/20 mg, or ROSUV 20 mg for 16 weeks. All patients were assessed before and after treatment: primary outcomes were lipid peroxidation (LPO), and nitric oxide (NO) surrogate levels in plasma; secondary outcomes included NCS, neuropathic symptom scores, and metabolic parameters. Data were expressed as mean ± SD or SEM, frequencies, and percentages; we used nonparametric analysis. RESULTS: LPO levels were reduced in both statin arms after 16 weeks of treatment (p < 0.05 versus baseline), without changes in the placebo group. NO levels were not significantly affected by statin treatment, although a trend towards significance concerning increased NO levels was noted in both statin arms. No significant changes were observed for the NCS or composite scores. DISCUSSION: EZE/SIMV and ROSUV are superior to placebo in reducing LPO in subjects with T2DM suffering from polyneuropathy. This trial is registered with NCT02129231.


Assuntos
Neuropatias Diabéticas/tratamento farmacológico , Ezetimiba/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Rosuvastatina Cálcica/uso terapêutico , Sinvastatina/uso terapêutico , Método Duplo-Cego , Ezetimiba/administração & dosagem , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Masculino , Pessoa de Meia-Idade , Rosuvastatina Cálcica/administração & dosagem , Sinvastatina/administração & dosagem
17.
Pharmacol Res ; 100: 309-20, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26303816

RESUMO

We have provided evidence that the stimulatory effects of (-)-epicatechin ((-)-EPI) on endothelial cell nitric oxide (NO) production may involve the participation of a cell-surface receptor. Thus far, such entity(ies) has not been fully elucidated. The G protein-coupled estrogen receptor (GPER) is a cell-surface receptor that has been linked to protective effects on the cardiovascular system and activation of intracellular signaling pathways (including NO production) similar to those reported with (-)-EPI. In bovine coronary artery endothelial cells (BCAEC) by the use of confocal imaging, we evidence the presence of GPER at the cell-surface and on F-actin filaments. Using in silico studies we document the favorable binding mode between (-)-EPI and GPER. Such binding is comparable to that of the GPER agonist, G1. By the use of selective blockers, we demonstrate that the activation of ERK 1/2 and CaMKII by (-)-EPI is dependent on the GPER/c-SRC/EGFR axis mimicking those effects noted with G1. We also evidence by the use of siRNA the role that GPER has on mediating ERK1/2 activation by (-)-EPI. GPER appears to be coupled to a non Gαi/o or Gαs, protein subtype. To extrapolate our findings to an ex vivo model, we employed phenylephrine pre-contracted aortic rings evidencing that (-)-EPI can mediate vasodilation through GPER activation. In conclusion, we provide evidence that suggests the GPER as a potential mediator of (-)-EPI effects and highlights the important role that GPER may have on cardiovascular system protection.


Assuntos
Catequina/farmacologia , Células Endoteliais/efeitos dos fármacos , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Actinas/metabolismo , Animais , Artérias/efeitos dos fármacos , Artérias/metabolismo , Bovinos , Células Cultivadas , Células Endoteliais/metabolismo , Estrogênios/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Masculino , Óxido Nítrico/metabolismo , Fenilefrina/farmacologia , Ratos , Ratos Wistar , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
18.
Food Funct ; 6(3): 824-33, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25598082

RESUMO

(-)-Epicatechin ((-)-EPI), a naturally occurring flavanol, has emerged as a likely candidate for cocoa-based product reported reductions in cardiometabolic risk. The present study aimed to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of purified (-)-EPI administered to healthy volunteers. In this phase I, open-label, two-part single- and multiple-dose study, subjects received either a single dose (n = 9) of 50, 100 or 200 mg or multiple doses (n = 8) of 50 mg daily (q.d.) or twice daily (b.i.d) for 5 days. Blood was collected at 0, 0.5, 1, 2, 4 and 6 h after (-)-EPI administration in the single and multiple dose groups (blood collection repeated in day 5). Samples were analyzed by HPLC-HR-ESI-MS for EPI and metabolite quantification. In the q.d. and b.i.d. groups, blood samples were analyzed for NO surrogates and follistatin levels as well as, platelet mitochondrial complexes I, V and citrate synthase activity levels. (-)-EPI was well tolerated and readily absorbed with further phase 2 metabolism. On day 5, in the q.d. and b.i.d. groups, there were significant increases in plasma nitrite of 30% and 17%, respectively. In the q.d. group on day 5 vs. day 1, platelet mitochondrial complexes I, IV and citrate synthase activities demonstrated a significant increase of ∼92, 62 and 8%, respectively. Average day 5 follistatin AUC levels were ∼2.5 fold higher vs. day 1 AUC levels in the b.i.d. group. (-)-EPI was safe to use, with no observed adverse effects, and our findings suggest that increases in NO metabolites, mitochondrial enzyme function and plasma follistatin levels may underlie some of the beneficial effects of cocoa products or (-)-EPI as reported in other studies.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/metabolismo , Doenças Cardiovasculares/prevenção & controle , Catequina/efeitos adversos , Catequina/metabolismo , Suplementos Nutricionais/efeitos adversos , Absorção Intestinal , Adulto , Idoso , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/sangue , Biomarcadores/sangue , Biomarcadores/metabolismo , Plaquetas/enzimologia , Doenças Cardiovasculares/imunologia , Catequina/administração & dosagem , Catequina/sangue , Citrato (si)-Sintase/química , Citrato (si)-Sintase/metabolismo , Suplementos Nutricionais/análise , Complexo de Proteínas da Cadeia de Transporte de Elétrons/agonistas , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Folistatina/sangue , Folistatina/metabolismo , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/agonistas , Óxido Nítrico/sangue , Óxido Nítrico/metabolismo , Testes de Toxicidade Subcrônica , Adulto Jovem
19.
J Gerontol A Biol Sci Med Sci ; 70(11): 1370-8, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25143004

RESUMO

There is evidence implicating oxidative stress (OS) as the cause of the deleterious effects of aging. In this study, we evaluated the capacity of the flavanol (-)-epicatechin (Epi) to reduce aging-induced OS and restore mitochondrial biogenesis, as well as, structural and functional endpoints in aged mice. Senile (S; 26-month-old) C57BL/6 male mice were randomly assigned to receive either water (vehicle) or 1mg/kg of Epi via oral gavage (twice daily) for 15 days. Young (Y; 6-month-old) mice were used as controls. In S brain, kidney, heart, and skeletal muscle (compared with Y animals) an increase in OS was observed as evidenced by increased protein-free carbonyls and decreased reduced glutathione levels as well as sirtuin 3, superoxide dismutase 2, catalase, thioredoxin and glutathione peroxidase protein levels. Well-recognized factors (eg, sirtuin 1) that regulate mitochondrial biogenesis and mitochondrial structure- and/or function-related endpoints (eg, mitofilin and citrate synthase) protein levels were also reduced in S organs. In contrast, the aging biomarker senescence-associated ß-galactosidase was increased in S compared with Y animals, and Epi administration reduced levels towards those observed in Y animals. Altogether, these data suggest that Epi is capable of shifting the biology of S mice towards that of Y animals.


Assuntos
Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Catequina/farmacologia , Biogênese de Organelas , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Fatores Etários , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Citrato (si)-Sintase/metabolismo , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Oxirredutases/metabolismo , beta-Galactosidase/metabolismo
20.
Materials (Basel) ; 8(3): 867-883, 2015 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-28787976

RESUMO

Titanium (Ti) and its alloys are amongst the most commonly-used biomaterials in orthopedic and dental applications. The Ti-aluminum-vanadium alloy (Ti6Al4V) is widely used as a biomaterial for these applications by virtue of its favorable properties, such as high tensile strength, good biocompatibility and excellent corrosion resistance. TiO2 nanotube (NTs) layers formed by anodization on Ti6Al4V alloy have been shown to improve osteoblast adhesion and function when compared to non-anodized material. In his study, NTs were grown on a Ti6Al4V alloy by anodic oxidation for 5 min using a super-oxidative aqueous solution, and their in vitro biocompatibility was investigated in pig periosteal osteoblasts and cartilage chondrocytes. Scanning electron microscopy (SEM), energy dispersion X-ray analysis (EDX) and atomic force microscopy (AFM) were used to characterize the materials. Cell morphology was analyzed by SEM and AFM. Cell viability was examined by fluorescence microscopy. Cell adhesion was evaluated by nuclei staining and cell number quantification by fluorescence microscopy. The average diameter of the NTs was 80 nm. The results demonstrate improved cell adhesion and viability at Day 1 and Day 3 of cell growth on the nanostructured material as compared to the non-anodized alloy. In conclusion, this study evidences the suitability of NTs grown on Ti6Al4V alloy using a super-oxidative water and a short anodization process to enhance the adhesion and viability of osteoblasts and chondrocytes. The results warrant further investigation for its use as medical implant materials.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...